Endothelial calcium firing mediates the extravasation of metastatic tumor cells
Metastatic dissemination is driven by genetic, biochemical, and biophysical cues that favor the distant colonization of organs and the formation of life-threatening secondary tumors. We have previously demonstrated that endothelial cells (ECs) actively remodel during extravasation by enwrapping arrested tumor cells (TCs) and extruding them from the vascular lumen while maintaining perfusion. In this work, we dissect the cellular and molecular mechanisms driving endothelial remodeling. Using high-resolution intravital imaging in zebrafish embryos, we demonstrate that the actomyosin network of ECs controls tissue remodeling and subsequent TC extravasation. Furthermore, we uncovered that this cytoskeletal remodeling is driven by altered endothelial-calcium (Ca<sup>2+</sup>) signaling caused by arrested TCs. Accordingly, we demonstrated that the inhibition of voltage-dependent calcium L-type channels impairs extravasation. Lastly, we identified P2X4, TRP, and Piezo1 mechano-gated Ca<sup>2+</sup> channels as key mediators of the process. These results further highlight the central role of endothelial remodeling during the extravasation of TCs and open avenues for successful therapeutic targeting.
Authors
- Annabel Larnicol (ORCID: https://orcid.org/0000-0002-2312-9961)
- Jacky G. Goetz (ORCID: https://orcid.org/0000-0003-2842-8116)
- Tristan Stemmelen (ORCID: https://orcid.org/0000-0002-4382-1277)
- Amandine Dupas (ORCID: https://orcid.org/0009-0001-0846-6011)
- Ruchi Goswami (ORCID: https://orcid.org/0000-0001-9724-2898)
- Olivier Lefèbvre (ORCID: https://orcid.org/0000-0001-9130-9174)
- Marina Peralta (ORCID: https://orcid.org/0000-0002-4206-4606)
- Raphaël Carapito (ORCID: https://orcid.org/0000-0002-7036-442X)
- Anne Molitor (ORCID: https://orcid.org/0000-0003-1646-2325)
- Naël Osmani (ORCID: https://orcid.org/0000-0003-1195-753X)
- Salvatore Girardo (ORCID: https://orcid.org/0000-0002-5350-0186)
Institutions
- Inserm (FR)
- Max Planck Institute for the Science of Light (DE)
- Hôpitaux Universitaires de Strasbourg (FR)
- Hôpital Civil, Strasbourg (FR)
- Université de Strasbourg (FR)
Publication Details
- Journal
- iScience
- Published
- 2024-12-26
- DOI
- https://doi.org/10.1016/j.isci.2024.111690
- Citations
- 12
- Primary Topic
- Erythrocyte Function and Pathophysiology
- Type
- article
- Field-Weighted Citation Impact
- 3.92
Funders
- Ministère de l'Enseignement supérieur, de la Recherche et de l'Innovation
- Alliance Nationale pour les Sciences de la Vie et de la Santé
- European Commission
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Université de Strasbourg
- Ligue Contre le Cancer
- Centre National de la Recherche Scientifique
- Institut National Du Cancer
- National Cancer Institute